Abstract 2130: Lipid and immune-based biomarkers associated with clinical response to TPST-1120: A small molecule antagonist of peroxisome-proliferator activated receptor-alpha
Authors: Nathan E. Standifer, Yonchu Jenkins, Sam Whiting, Thomas W. Dubensky
Journal: Cancer Research (2023)

Abstract Background: TPST-1120 is a small molecule antagonist of peroxisome-proliferator activated receptor-alpha (PPAR-α), a regulator of fatty acid oxidation and immune suppression. TPST-1120 was well tolerated and showed signs of activity in a phase I trial as monotherapy and in combination with nivolumab (NCT03829436). The objective response rate was 30% (3/10, all partial responses) in subjects treated at the two highest TPST-1120 doses in combination with nivolumab and included two subjects with renal cell carcinoma previously refractory to anti-PD-1 therapy [1]. We performed ctDNA mutational analysis at baseline and quantified lipid and gene expression changes in post-treatment whole blood to identify potential biomarkers of response. Methods: Mutational analysis of ctDNA was assessed using the PredicineCARE™ assay (Predicine Inc.), and lipid analysis was performed by tandem mass spectrometry. Gene expression changes were quantified using the nCounter® PanCancer Immune Profiling panel (NanoString Inc.) supplemented with 30 PPAR-α target genes. Putative clinical response biomarkers were identified as those differentially expressed by patients with partial response (PR) compared to those with progressive disease (p&amp;lt;0.05 by Mann-Whitney U Test). Longitudinal lipid change magnitudes were assessed by Wilcoxon paired analysis (p&amp;lt;0.05). Results: Baseline ctDNA mutational analysis revealed that patients with PR or stable disease were more likely to bear mutations in isocitrate dehydrogenase (IDH) and phosphatase and tensin homolog (PTEN) compared to patients with progressive disease. Patients with PR demonstrated significant elevations (p&amp;lt;0.05) in multiple genes including those associated with lipid transport (APOE), Th17 development (RORC) and down-regulation of CD155, a TIGIT ligand. Lipid analysis demonstrated acute changes in free fatty acids (FFA) four hours after first dose (p&amp;lt;0.05). Among patients receiving combination therapy, the highest post-dose elevations in FFA, lysophosphatidylcholine and lysophosphatidylethanolamine levels were observed in a PR patient exhibiting the longest duration of response. Conclusions: TPST-1120 treated patients with PR demonstrated fatty acid oxidation perturbations and immune gene expression changes as potential biomarkers of clinical benefit. Increased frequencies of responding patients bearing PI3K pathway or IDH mutations may reveal populations likely to benefit from treatment with TPST-1120. 1. Yarchoan M, et al., “A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in patients with advanced solid tumors.” Journ. Clin. Onc. 2022; 40 (16) suppl. Citation Format: Nathan E. Standifer, Yonchu Jenkins, Sam Whiting, Thomas W. Dubensky. Lipid and immune-based biomarkers associated with clinical response to TPST-1120: A small molecule antagonist of peroxisome-proliferator activated receptor-alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2130.